Project1-ProjectSummary Numerousnuclearreceptors(NRs)ortranscriptionfactors(TFs)havebeenidentifiedasimportantregulatorsof bodyweight.However,anti-obesityregimenstargetingtheseindividualmoleculesalonearefarfromsatisfying. Coactivators interact with a broad range of NRs/TFs and may serve as master regulators that coordinate and synergizeactionsofmultiplemetabolicsignals.HighlevelsofSteroidReceptorCoactivator-1and-2(SRC-1and SRC-2)areexpressedinthehypothalamus,thekeybrainregioncontrollingfeedingandbodyweightbalance. ThepilotobservationsledtoahypothesisthathypothalamicSRC-1andSRC-2coactivateSTAT3andFoxO1, repectively, to provide coordinated control of energy metabolism. Aim 1 will determine whether hypothalamic SRC-1fine-tunesSTAT3transcriptionactivitytomediatetheanti-obesityeffectsofleptin.Mousemodelslacking or overexpressing SRC-1 only in leptin-responsive neurons have been generated. Metabolic parameters in response to different diets or to leptin treatment will be assessed in these mice. Importantly, the molecular mechanisms by which the SRC1-pSTAT3 complex regulates leptin signaling will be delineated. Aim 2 will determine whether human SRC-1 mutations impair leptin-STAT3 pathway in the hypothalamus and cause obesity. Using the CRISPR technology, a knockin mouse line has been generated to mimic a SRC-1 genetic mutationassociatedwithhumanobesity.Metabolicphenotypesofthesemicewillbecharacterized,andleptin- STAT3 actions and STAT3 transcription activity will be evaluated. Aim 3 will determine whether hypothalamic SRC-2coativatesFoxO1transcriptionalactivitytofacilitateenergyreservations.Micelackingoroverexpressing SRC-2 in mature POMC neurons have been generated, with/without FoxO1 overexpression. Metabolic phenotypeswillbecharacterizedinallthesemodelsandFoxO1transcriptionalactivitywillalsobeevaluated.